A Study Evaluating the Efficacy of Obinutuzumab and Bendamustine Treatment in Participants With Refractory or Relapsed Chronic Lymphocytic Leukemia

ORR was defined as percentage of participants achieving Complete Response (CR), incomplete CR (CRi) or Partial Response (PR). CR: lymphocytes below 4 x 10\^9/L, absence of lymphadenopathy, hepatomegaly and splenomegaly, absence of disease or constitutional symptoms, neutrophils \> 1.5 x 10\^9/L, platelets \> 100 x 10\^9/L, hemoglobin \> 110 g/L, bone marrow at least normocellular for age. CRi: CR with persistent cytopenia, i.e. anemia, thrombocytopenia and/or neutropenia. PR: reduction ≥ 50% of the lymphocyte count AND reduction ≥ 50% of the lymphadenopathy OR reduction ≥ 50% of the size of the liver if enlarged at baseline OR reduction ≥ 50% of the size of the spleen if enlarged at baseline PLUS one of the following: neutrophils \> 1.5 x 10\^9/L, platelets \> 100 x 10\^9/L, hemoglobin \> 110 g/L or increase ≥ 50% compared to pre-treatment.

Time frame: 2-3 months after last dose of the study treatment (up to approximately 9 months)

Population: Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab).

Best overall response was defined as percentage of participants achieving a best response of CR, CRi and PR. CR: lymphocytes below 4 x 10\^9/L, absence of lymphadenopathy, hepatomegaly and splenomegaly, absence of disease or constitutional symptoms, neutrophils \> 1.5 x 10\^9/L, platelets \> 100 x 10\^9/L, hemoglobin \> 110 g/L, bone marrow at least normocellular for age. CRi: CR with persistent cytopenia, i.e. anemia, thrombocytopenia and/or neutropenia. PR: reduction ≥ 50% of the lymphocyte count AND reduction ≥ 50% of the lymphadenopathy OR reduction ≥ 50% of the size of the liver if enlarged at baseline OR reduction ≥ 50% of the size of the spleen if enlarged at baseline PLUS one of the following: neutrophils \> 1.5 x 10\^9/L, platelets \> 100 x 10\^9/L, hemoglobin \> 110 g/L or increase ≥ 50% compared to pre-treatment.

Time frame: During study treatment and until 6 months after end of study treatment at approximately 12 months

Population: Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab). Reported here is the number of participants for whom data for best response achieved were available.

DFS was defined for all participants who achieved complete response (CRi or CR). DFS lasted from the date on which CRi or CR was recorded until the date on which the first DP or death from any cause occurred. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10\^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10\^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10\^9/L if the marrow biopsy also shows infiltration of clonal CLL cells.

Time frame: From occurrence of complete response up to disease progression or death, whichever occurred first (up to approximately 4.5 years)

Population: Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab). Included in the analysis are participants who achieved CRi or CR.

DR was defined for participants with CRi, CR or PR. DR spanned from the date on which response was recorded until the date on which DP or death from any cause occurred. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10\^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10\^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10\^9/L if the marrow biopsy also shows infiltration of clonal CLL cells.

Time frame: From occurrence of CR or PR up to disease progression or death, whichever occurred first (up to approximately 4.5 years)

Population: Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab). Included in the analysis are participants who achieved CRi, CR or PR.

EFS was defined as the time from the start of treatment to DP/relapse, death from any cause or start of a new anti-leukemia therapy. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10\^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10\^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10\^9/L if the marrow biopsy also shows infiltration of clonal CLL cells.

Time frame: From start of treatment up to disease progression or relapse or death or start of a new anti-leukemic therapy, whichever occurred first (up to approximately 4.5 years)

Population: Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab).

OS was defined as the time from the start of study treatment to death from any cause.

Time frame: From start of treatment up to death of any cause (up to approximately 4.5 years)

Population: Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab).

Time frame: Up to end of treatment at 6 months

Population: Safety population included all participants, who received at least one dose of any treatment.

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs. An SAE was any AE that was any of the following: fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/ birth defect, and was considered a significant medical event by the investigator.

Time frame: Up to approximately 4.5 years

Population: Safety population included all participants, who received at least one dose of any treatment.

AESIs included any of the following: SAEs associated with the infusion of obinutuzumab: obinutuzumab serious infusion-related reactions, which were defined as AEs occurring during or within 24 hours following the administration of an infusion of obinutuzumab and considered related to obinutuzumab; serious infection; serious neutropenia; any tumor lysis syndrome (TLS); second malignancies.

Time frame: Up to approximately 4.5 years

Population: Safety population included all participants, who received at least one dose of any treatment.

Concomitant therapies included any medication (prescription medication, over-the-counter medications, herbal/homeopathic remedies, nutritional supplements) used by subjects in the 7 days prior to screening until the end of treatment. The following treatments were not permitted during the study treatment period: investigational or unauthorized or unapproved medicinal products, immunotherapy or radioimmunotherapy (other than the trial immunotherapy, obinutuzumab), chemotherapy (other than the trial chemotherapy, bendamustine) and radiotherapy.

Time frame: From 7 days prior to screening to the end of treatment at 6 months

Population: Safety population included all participants, who received at least one dose of any treatment.

IRRs were defined as AEs occurring during or within 24 hours following the administration of an infusion and considered related to drug treatment.

Time frame: Up to end of treatment at 6 months

Population: Safety population included all participants, who received at least one dose of any treatment.

MRD negativity was defined as the presence of less than 1 cell of CLL per 10,000 leukocytes (= category 0, \<0.01%) assessed in bone marrow (BM) and peripheral blood (PB) by flow cytometry after the end of the treatment at the final response assessment.

Time frame: At approximately 9 months

Population: ITT population included all participants, who received at least one dose of any treatment.

Time frame: Up to approximately 4.5 years

Population: Safety population included all participants, who received at least one dose of any treatment.

PFS is defined as the time from the start of treatment to disease progression (DP), relapse or death from any cause, whichever occurs first, as assessed by the investigator. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10\^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10\^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10\^9/L if the marrow biopsy also shows infiltration of clonal chronic lymphocytic leukemia (CLL) cells.

Time frame: From start of treatment up to disease progression or relapse or death, whichever occurred first (up to approximately 4.5 years)

Population: Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab).

Time to re-treatment/new leukemia therapy was defined as the time between the start of treatment and the date of the first administration of re-treatment or new leukemia therapy.

Time frame: Up to 4.5 years

Population: Efficacy population included all participants, who received at least one dose of both treatments (bendamustine and obinutuzumab).